Role of Histamine in Narcolepsy/EDS Disorders R03 small research grants are designed for short-term, high impact, low cost studies. The goal of this proposed work is to extend on preliminary data indicating low CSF histamine levels in disorders of excessive daytime sleepiness. We will also study diurnal fluctuation in CSF histamine levels in normal, healthy volunteers. An increasing number of animal studies suggest that histamine plays a major role in regulating alertness. This may be relevant to narcolepsy since hypocretin stimulates histaminergic transmission and narcoleptic canines with deficient hypocretin transmission also have low central nervous histamine contents. We also have preliminary data from two sources (our own samples and from a Japanese collaborator) indicating low CSF histamine in human narcolepsy-cataplexy with hypocretin deficiency. Most interestingly however, we also found decreased CSF histamine in a subset of patients with daytime sleepiness, but in the context of normal hypocretin levels, for example with idiopathic hypersomnia. Patients with daytime sleepiness associated with sleep apnea had normal levels. This exciting preliminary result suggests that histamine may play a role in the pathophysiology of non-hypocretin dependent syndrome of centrally- mediated hypersomnolence. Our goal will be to extend this dataset using a large number of existing CSF samples. We will also conduct exploratory statistical analysis to study clinical predictors of low CSF histamine levels. Whether or not this change is primary or secondary to daytime sleepiness in these patients will be explored by further grant applications once the preliminary finding is confirmed and additional exploratory analysis have been conducted. As almost nothing is known on the pathophysiology of non- hypocretin deficient hypersomnias, we believe this work to be ideally suited for a small grant application. [unreadable] [unreadable] [unreadable]